HOMOCYSTEINE AND CONGENITAL HEART DEFECTS

补充叶酸与圆锥干、口面和神经管缺陷的显著减少有关。氨基酸同型半胱氨酸随着叶酸缺乏而增加，并且升高的同型半胱氨酸本身似乎是这些缺陷的危险因素。我们最近的研究已经导致的假设，同型半胱氨酸可能会扰乱神经嵴和神经管发育作为一种拮抗剂的N-甲基-D-天冬氨酸谷氨酸受体（NMDAR）。事实上，神经嵴和神经管异常的一些最知名的风险因素也是NMDAR拮抗剂。目前的建议将测试的假设，同型半胱氨酸诱导锥干和相关的缺陷，作为一个NMDAR拮抗剂。鸡和小鼠胚胎模型都将用于这些实验。该提议有三个目的：目的1，检验NMDAR激动剂将拯救同型半胱氨酸处理的胚胎的假设，相反，外源性NMDAR拮抗剂将与同型半胱氨酸协同相互作用，加剧正常发育的破坏。目的2，在同型半胱氨酸和外源性NMDAR拮抗剂干扰神经嵴迁移和神经管闭合过程中关键基因表达的假设中，验证同型半胱氨酸和外源性NMDAR拮抗剂干扰关键基因表达的假设。目的2，探讨同型半胱氨酸和外源性NMDAR拮抗剂对神经嵴细胞功能的影响。该提案提供了第一个统一的假设，关于一组重要的异常发育风险因素的机制，包括治疗和娱乐药物，环境污染物和低叶酸。一个共同的作用机制将表明，这些因素可能会以先前未预料到的方式相互作用。这个建议将开始探索基因/环境相互作用在诱导这些异常中的作用。虽然叶酸补充剂会导致更少的异常，但最有效和最全面的预防策略将通过彻底了解异常发育的机制来实现。

Supplemental folic acid is associated with significant decreases in conotruncal, orofacial, and neural tube defects. The amino acid homocysteine increases with folate deficiency, and elevated homocysteine per se appears to be a risk factor for these defects. Our recent studies have led to the hypothesis that homocysteine may perturb neural crest and neural tube development by acting as an antagonist for the N-methyl-D-aspartate glutamate receptor (NMDAR). Indeed, some of the best known risk factors for neural crest and neural tube abnormalities also are NMDAR antagonist. The present proposal will test the hypothesis that homocysteine induces conotruncal and related defects by acting as an NMDAR antagonist. Both the chicken and the mouse embryo models will be employed in these experiments. There are three aims of this proposal: Aim 1, to test the hypotheses that NMDAR agonists will rescue homocysteine-treated embryos, and conversely, that exogenous NMDAR antagonists will interact synergistically with homocysteine to exacerbate the disruption of normal development. Aim 2, to test the hypothesis that homocysteine and exogenous NMDAR antagonists disrupt the expression of key genes during hypothesis that homocysteine and exogenous NMDAR antagonists disrupt the expression of key genes during neural crest migration and neural tube closure. Aim 2, to determine the effect of homocysteine and exogenous NMDAR antagonists on neural crest cell functions. This proposal offers the first unifying hypothesis regarding a mechanism for a set of important risk factors for abnormal development that includes therapeutic and recreational drugs, environmental contaminants, and low folate. A common mechanism of actions would show that these factors may interact in previous unsuspected ways. This proposal will begin to explore the role of gene/environment interactions in the induction of these abnormalities. Although folate supplements will result in fewer abnormalities, the most effective and comprehensive prevention strategies will come through a thorough understanding of the mechanisms that underlie abnormal development..